Inhalation Exposure Model Research Articles

Evaluation of the ECETOC TRA model for workplace inhalation exposure to ethylbenzene in Japan

The European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) that is positioned as a Tier 1 model for screening assessment in Europe can contribute to improvement of the independent work environment of workers if utilized in Japanese workplaces. In this study, estimated values of ethylbenzene obtained using ECETOC TRA were compared to measured values, and applicability of ECETOC TRA to the Japanese workplace was studied. Measured values and the work content collected from exposure field surveys conducted by the Japanese government in FY 2009 and FY 2010 were utilized for this study. The 137 tasks in 17 companies evaluated were related to manufacturing and painting. The process categories (PROCs) related to ECETOC TRA were selected for manufacturing (PROC 2, 3, 4, 5, 8a, 8b, 9, 13, 14 or 15) and painting (PROC 7 or 10). The results showed that most of the estimated values of manufacturing work were above the measured values, and just 3 of 52 tasks were below the measured values. On the other hand, the estimated values of painting work below the measured values were observed in 27 of 85 tasks. In particular, it was observed that the estimated values were below the measured values in 22 of 38 tasks for roller painting work (PROC 10). The 24 tasks for which 20 ppm was exceeded were related to painting work, and 4 of 10 tasks for PROC 7 and 13 of 14 tasks for PROC 10 were below the estimated values. All of the work for which the estimated values were below the measured values consisted of the hull block painting in ship building work. Though the painting work performed at indoor workplaces in Japan was subject to regulations for ethylbenzene in 2013 and reduction measures are being developed, independent risk assessment and management by workers is required continuously at workplaces engaged in the production of ethylbenzene. ECETOC TRA can be adequately utilized as a Tier 1 model for screening assessment to perform independent risk assessment at Japanese workplaces engaged in the production of ethylbenzene.

Assessment of inhaled acute ammonia-induced lung injury in rats

This study examined acute toxicity and lung injury following inhalation exposure to ammonia. Male Sprague-Dawley rats (300–350 g) were exposed to 9000, 20 000, 23 000, 26 000, 30 000 or 35 000 ppm of ammonia for 20 min in a custom head-out exposure system. The exposure atmosphere, which attained steady state within 3 min for all ammonia concentrations, was monitored and verified using a Fourier transform infrared spectroscopy (FTIR) gas analyzer. Animals exposed to ammonia resulted in dose-dependent increases in observed signs of intoxication, including increased chewing and licking, ocular irritation, salivation, lacrimation, oronasal secretion and labored breathing. The LCt50 of ammonia within this head-out inhalation exposure model was determined by probit analysis to be 23 672 ppm (16 489 mg/m3) for the 20 min exposure in male rats. Exposure to 20 000 or 23 000 ppm of ammonia resulted in significant body weight loss 24-h post-exposure. Lung edema increased in all ammonia-exposed animal groups and was significant following exposure to 9000 ppm. Bronchoalveolar fluid (BALF) protein concentrations significantly increased following exposure to 20 000 or 23 000 ppm of ammonia in comparison to controls. BAL cell (BALC) death and total cell counts increased in animals exposed to 20 000 or 23 000 ppm of ammonia in comparison to controls. Differential cell counts of white blood cells, neutrophils and platelets from blood and BALF were significantly increased following exposure to 23 000 ppm of ammonia. The following studies describe the validation of a head-out inhalation exposure model for the determination of acute ammonia-induced toxicity; this model will be used for the development and evaluation of potential therapies that provide protection against respiratory and systemic toxicological effects.

Vapor inhalation exposure to soman in conscious untreated rats: preliminary assessment of neurotoxicity

Neurological toxicity and brain injury following vapor inhalation exposure to the chemical warfare nerve agent (CWNA) soman (GD) were examined in untreated non-anesthetized rats. In this study, male Sprague-Dawley rats (300–350 g) were exposed to 600 mg × min/m3 of soman or vehicle in a customized head-out inhalation system for 7 min. Convulsant animals were observed for clinical signs and various regions of the brain (dorsolateral thalamus, basolateral amygdala, piriform cortex, and lateral cortex) were collected for pathological observations 24 h post-exposure. Signs of CWNA-induced cholinergic crises including salivation, lacrimation, increased urination and defecation, and tremors were observed in all soman-exposed animals. Soman-exposed animals at 24 h post-exposure lost 11% of their body weight in comparison to 2% in vehicle-exposed animals. Whole blood acetylcholinesterase (AChE) activity was significantly inhibited in all soman-exposed groups in comparison to controls. Brain injury was confirmed by the neurological assessment of hematoxylin-eosin (H&E) staining and microscopy in the piriform cortex, dorsolateral thalamus, basolateral amygdala, and lateral cortex. Severe damage including prominent lesions, edematous, congested, and/or hemorrhagic tissues was observed in the piriform cortex, dorsolateral thalamus, and lateral cortex in soman-exposed animals 24 h post-exposure, while only minimal damage was observed in the basolateral amygdala. These results indicate that inhalation exposure to soman vapor causes neurological toxicity and brain injury in untreated unanesthetized rats. This study demonstrates the ability of the described soman vapor inhalation exposure model to cause neurological damage 24 h post-exposure in rats.

Inhalation exposure model of hydrogen sulfide (H₂S)-induced hypometabolism in the male Sprague-Dawley rat.

Hydrogen sulfide (H2S) has been accepted as a physiologically relevant cell-signaling molecule with both toxic and beneficial effects depending on its concentration in mammalian tissues. Notably, exposure to H2S in breathable air has been shown to decrease aerobic metabolism and induce a reversible hypometabolic-like state in laboratory rodent models. Herein, we describe an experimental exposure setup that can be used to define the reversible cardiovascular and metabolic physiology of rodents (rats) during H2S-induced hypometabolism and following recovery.

Whole genome expression analysis in primary bronchial epithelial cells after exposure to sulphur mustard

Sulphur mustard (SM) is a highly toxic chemical agent and poses a current threat to both civilians and military personnel in the event of a deliberate malicious release. Acute SM toxicity develops over the course of several hours and mainly affects the skin and mucosal surfaces of the eyes and respiratory system. In cases of acute severe exposure, significant lung injury can result in respiratory failure and death. Systemic levels of SM can also be fatal, frequently due to immunodepletion and the subsequent development of secondary infections. Whilst the physical effects associated with SM exposure are well documented, the molecular mechanisms mediating these changes are poorly understood, hindering the development of an effective therapeutic strategy. To gain a better understanding of the mechanism of SM toxicity, this study investigated whole genome transcriptional changes after SM in primary human bronchial epithelial cells, as a model for inhalation exposure. The analysis revealed >400 transcriptional changes associated with SM exposure. Pathways analysis confirmed the findings of previous studies suggesting that DNA damage, cell cycle arrest, cell death and inflammation were important components of SM toxicity. In addition, several other interesting observations were made, suggesting that protein oxidation as well as effects on the mitotic apparatus may contribute to SM toxicity.

Assessing the risk of Legionnaires’ disease: The inhalation exposure model and the estimated risk in residential bathrooms

Legionella are widely found in the built environment. Patients with Legionnaires’ disease have been increasing in Japan; however, health risks from Legionella bacteria in the environment are not appropriately assessed. We performed a quantitative health risk assessment modeled on residential bathrooms in the Adachi outbreak area and estimated risk levels. The estimated risks in the Adachi outbreak approximately corresponded to the risk levels exponentially extrapolated into lower levels on the basis of infection and mortality rates calculated from actual outbreaks, suggesting that the model of Legionnaires’ disease in residential bathrooms was adequate to predict disease risk for the evaluated outbreaks. Based on this model, the infection and mortality risk levels per year in 10CFU/100ml (100CFU/L) of the Japanese water quality guideline value were approximately 10−2 and 10−5, respectively. However, acceptable risk levels of infection and mortality from Legionnaires’ disease should be adjusted to approximately 10−4 and 10−7, respectively, per year. Therefore, a reference value of 0.1CFU/100ml (1CFU/L) as a water quality guideline for Legionella bacteria is recommended. This value is occasionally less than the actual detection limit. Legionella levels in water system should be maintained as low as reasonably achievable (<1CFU/L).

A Comparison of Screening and Refined Exposure Models for Evaluating Toluene Air Emissions from a Washing Machine

ABSTRACT Residential clothes washing machines are potential air emission sources for volatile organic compounds (VOCs). The U.S. Environmental Protection Agency has a screening model to predict the potential inhalation exposure to VOC emissions from a washing machine into room air. They also have a refined exposure model that can be extrapolated to evaluate a washing machine. The objectives of this study were to evaluate the screening and refined models and to compare their predictions to experimental results for toluene-contaminated tap water. This study identified a number of important results and it explained why the models over predicted as well as the models’ limitations. The Exposure and Fate Screening Tool (EFAST) Consumer Exposure Module (CEM) screening model predicted the peak concentration was 340% of the experimental result and that 90% of the toluene mass was emitted. The refined Simulation Tool Kit for Indoor Air Quality and Inhalation Exposure (IAQX) model predicted the peak concentration was 35% higher than the experimental value, the Time Weighted Average (TWA)-30 min concentration was 45% higher, and about 30% of the toluene mass was emitted. The screening model provided a quick, conservative exposure result with several limitations. The refined model provided a better estimate of the potential exposure but it required more input data and effort.

Host stress and immune responses during aerosol challenge of Brown Norway rats with Yersinia pestis

Inhalation exposure models are becoming the preferred method for the comparative study of respiratory infectious diseases due to their resemblance to the natural route of infection. To enable precise delivery of pathogen to the lower respiratory tract in a manner that imposes minimal biosafety risk, nose-only exposure systems have been developed. Early inhalation exposure technology for infectious disease research grew out of technology used in asthma research where predominantly the Collison nebulizer is used to generate an aerosol by beating a liquid sample against glass. Although infectious aerosol droplets of 1–5 μm in size can be generated, the Collison often causes loss of viability. In this work, we evaluate a gentler method for aerosolization of living cells and describe the use of the Sparging Liquid Aerosol Generator (SLAG) in a rat pneumonic plague model. The SLAG creates aerosols by continuous dripping of liquid sample on a porous metal disc. We show the generation of 0.5–1 μm Yersinia pestis aerosol particles using the SLAG with spray factors typically ranging from 10−7 to 10−8 with no detectable loss of bacterial viability. Delivery of these infectious particles via nose-only exposure led to the rapid development of lethal pneumonic plague. Further, we evaluated the effect of restraint-stress imposed by the nose-only exposure chamber on early inflammatory responses and bacterial deposition. Elevated serum corticosterone which peaked at 2 h post-procedure indicated the animals experienced stress as a result of restraint in the nose-only chamber. However, we observed no correlation between elevated corticosterone and the amount of bacterial deposition or inflammation in the lungs. Together these data demonstrate the utility of the SLAG and the nose-only chamber for aerosol challenge of rodents by Y. pestis.

Development of a physiologically based pharmacokinetic model for inhalation of jet fuels in the rat

The pharmacokinetic behavior of the majority of jet fuel constituents has not been previously described in the framework of a physiologically based pharmacokinetic (PBPK) model for inhalation exposure. Toxic effects have been reported in multiple organ systems, though exposure methods varied across studies, utilizing either vaporized or aerosolized fuels. The purpose of this work was to assess the pharmacokinetics of aerosolized and vaporized fuels, and develop a PBPK model capable of describing both types of exposures. To support model development, n-tetradecane and n-octane exposures were conducted at 89 mg/m3 aerosol+vapor and 1000–5000 ppm vapor, respectively. Exposures to JP-8 and S-8 were conducted at ~900–1000 mg/m3, and ~200 mg/m3 to a 50:50 blend of both fuels. Sub-models were developed to assess the behavior of representative constituents and grouped unquantified constituents, termed “lumps”, accounting for the remaining fuel mass. The sub-models were combined into the first PBPK model for petroleum and synthetic jet fuels. Inhalation of hydrocarbon vapors was described with simple gas-exchange assumptions for uptake and exhalation. For aerosol droplets systemic uptake occurred in the thoracic region. Visceral tissues were described using perfusion and diffusion-limited equations. The model described kinetics at multiple fuel concentrations, utilizing a chemical “lumping” strategy to estimate parameters for fractions of speciated and unspeciated hydrocarbons and gauge metabolic interactions. The model more accurately simulated aromatic and lower molecular weight (MW) n-alkanes than some higher MW chemicals. Metabolic interactions were more pronounced at high (~2700–1000 mg/m3) concentrations. This research represents the most detailed assessment of fuel pharmacokinetics to date.

Development of a Botulinum Neurotoxin animal inhalation model and evaluation of small molecule therapeutics for medical countermeasure

We have recently developed several small molecule inhibitors of Botulinum Neurotoxin (BoNT) using a fragment-based approach guided by structural data and computer-aided lead optimization. In vitro assay and cell-based assays showed that these are the most potent inhibitors described against BoNT to date. We are now evaluating the safety and efficacy of the lead inhibitors in a small animal model of BoNT inhalational exposure. Inhalation is the most likely form of delivery of BoNT if it is used as a biological weapon. Emerging data from other groups reveal severe impairment of several respiratory functional parameters following BoNT/A exposure and lack of protection by the pentavalent toxoid against pulmonary injury. We are adopting our microinstillation technology, which involves aerosolizing the toxin in the trachea using a microcatheter to develop a BoNT inhalation exposure model. The simplicity of the procedure and its requirement of only microliters of a toxin to generate a meaningful and reliable dose–response suggest that it may be a suitable method for acute inhalation toxicity evaluation of BoNT aerosol. Post-exposure respiratory functional analysis by plethysmography may identify sensitive non-invasive parameters for rapid and early diagnosis of BoNT exposure. Since the airway and lung is the primary target for inhaled BoNT and the lung pathology persists, development of a small animal inhalation model and evaluation of potent small molecule BoNT inhibitors is important to develop therapeutics to protect against both the pulmonary pathology as well as systemic toxicity in the event of an aerosol release.

Modeling population exposures to outdoor sources of hazardous air pollutants

Accurate assessment of human exposures is an important part of environmental health effects research. However, most air pollution epidemiology studies rely upon imperfect surrogates of personal exposures, such as information based on available central-site outdoor concentration monitoring or modeling data. In this paper, we examine the limitations of using outdoor concentration predictions instead of modeled personal exposures for over 30 gaseous and particulate hazardous air pollutants (HAPs) in the US. The analysis uses the results from an air quality dispersion model (the ASPEN or Assessment System for Population Exposure Nationwide model) and an inhalation exposure model (the HAPEM or Hazardous Air Pollutant Exposure Model, Version 5), applied by the US. Environmental protection Agency during the 1999 National Air Toxic Assessment (NATA) in the US. Our results show that the total predicted chronic exposure concentrations of outdoor HAPs from all sources are lower than the modeled ambient concentrations by about 20% on average for most gaseous HAPs and by about 60% on average for most particulate HAPs (mainly, due to the exclusion of indoor sources from our modeling analysis and lower infiltration of particles indoors). On the other hand, the HAPEM/ASPEN concentration ratio averages for onroad mobile source exposures were found to be greater than 1 (around 1.20) for most mobile-source related HAPs (e.g. 1, 3-butadiene, acetaldehyde, benzene, formaldehyde) reflecting the importance of near-roadway and commuting environments on personal exposures to HAPs. The distribution of the ratios of personal to ambient concentrations was found to be skewed for a number of the VOCs and reactive HAPs associated with major source emissions, indicating the importance of personal mobility factors. We conclude that the increase in personal exposures from the corresponding predicted ambient levels tends to occur near locations where there are either major emission sources of HAPs or when individuals are exposed to either on- or nonroad sources of HAPs during their daily activities. These findings underscore the importance of applying exposure-modeling methods, which incorporate information on time-activity, commuting, and exposure factors data, for the purposes of assigning exposures in air pollution health studies.

Modeling framework for human exposure assessment

We are at the dawn of a new era of quantitative consumer exposure and risk assessment of chemicals driven by regulatory mandates. This remarkable development also signals the beginning of a dramatic resurgence in the need for and development of human exposure models. This paper presents some of the philosophical background underlying exposure modeling in the context of human health risk assessment. The basic types of and structure of inhalation exposure models are discussed, as well as the research needed to move us forward into this exciting new period of development.

Inhalation Exposure Study of Titanium Dioxide Nanoparticles with a Primary Particle Size of 2 to 5 nm

BackgroundNanotechnology offers great promise in many industrial applications. However, little is known about the health effects of manufactured nanoparticles, the building blocks of nanomaterials.ObjectivesTitanium dioxide (TiO2) nanoparticles with a primary size of 2–5 nm have not been studied previously in inhalation exposure models and represent some of the smallest manufactured nanoparticles. The purpose of this study was to assess the toxicity of these nanoparticles using a murine model of lung inflammation and injury.Materials and MethodsThe properties of TiO2 nanoparticles as well as the characteristics of aerosols of these particles were evaluated. Mice were exposed to TiO2 nanoparticles in a whole-body exposure chamber acutely (4 hr) or subacutely (4 hr/day for 10 days). Toxicity in exposed mice was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase (LDH) activity and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Lungs were also evaluated for histopathologic changesResultsMice exposed acutely to 0.77 or 7.22 mg/m3 nanoparticles demonstrated minimal lung toxicity or inflammation. Mice exposed subacutely (8.88 mg/m3) and necropsied immediately and at week 1 or 2 postexposure had higher counts of total cells and alveolar macrophages in the BAL fluid compared with sentinels. However, mice recovered by week 3 postexposure. Other indicators were negative.ConclusionsMice subacutely exposed to 2–5 nm TiO2 nanoparticles showed a significant but moderate inflammatory response among animals at week 0, 1, or 2 after exposure that resolved by week 3 postexposure.

Development of an Exposure Control Efficiency Library (ECEL)

TS1-09 Abstract: Further development of advanced exposure tools is dependent on “evidence” that explains the effect of exposure determinants and risk management measures (RMM) on exposure. However, this information is generally scattered and time-consuming to obtain in literature. Exposure databases are generally inadequately formatted to allow the retrieval of this type of information. An exposure control efficiency library (ECEL) has been developed that collates the actual effects of exposure determinants within the context of a specific workplace scenario. Its application is 2-fold: first, to substantiate the effects of RMMs during the development of a new (advanced) inhalation exposure model; and second, to be used as an advisory tool that facilitates the selection of scenario-specific RMMs in industry. Two key issues were addressed before the development of ECEL, ie, standard scenarios and standard RMMs. Standard scenarios were adopted and applied in the form of so-called generic “operation units” (OUs). Each OU clusters tasks together with the same exposure process and underlying determinants. This classification can be used to study the effect of RMMs on groups of “similar” tasks or processes. A systematic classification system based on the “STOP principle” and combined with the “exposure process” (emission, transmission, immission) was devised to categorize exposure determinants and controls into “standard” RMMs. Entry fields in the database focused on a description of the workplace scenario before and after an intervention (or with and without a RMM). Each intervention is then translated into a “reduction factor” that expresses the quantitative effect on exposure levels. A simple guideline was put together to prioritize data according to its usefulness and quality (priority given to intervention studies and appropriate study designs). An extensive literature search revealed 260 studies suitable for entry. Studies included exposure field, intervention and experimental studies. Due to time/financial constraints, approximately 100 studies were entered, comprising some 600 entries. Each entry represents a “reduction factor” for a specified task, substance, and RMM. Approximately 250 entries concerned the effect of ventilation (of which 150 LEV). The most commonly found studies applied multivariate statistical analysis on exposure data to illustrate the quantitative effect of determinants. Some examples are given of the control efficacies of different RMMs and the possible benefit for modeling purposes is highlighted. The added value of the output is dependent on data availability. Possibilities to apply ECEL as an advisory tool to select optimal RMMs in industry have not yet been investigated.

Development of an Exposure Model and Related Exposure Database

TS1-18 Abstract: Several important issues promote the development of new exposure models for risk assessment. The upcoming REACH legislation and obvious shortcomings of EASE being among the most important drivers. Currently, we are working on a modification of a model for inhalation exposure originally developed by Cherrie and colleagues. This model includes generic parameters reflecting intrinsic emission, handling, and control. We propose a modification of the model to provide quantitative exposure estimates in a more transparent way. We envisage that this modified model can serve as an element in a new advanced tool that integrates deterministic model output and empiric exposure information. A central part in this development is a transparent classification of the handling and control parameters according to the so-called operation unit concept. This concept has first been used in the RISKOFDERM project to comprehensively organize dermal exposure scenarios. For inhalation exposure, we propose a comparable structure to cluster tasks or scenarios into operation units that represent similar exposure processes. We have currently defined 10 operation units; by default, the set of main exposure determinants varies for each operation unit. The main determinants are all related to level of energy, scale, and product-to-air interface of the process. Specific control measures are proposed for each operation unit. This structure enables the definition of operation unit-specific algorithms to describe inhalation exposure for distinct processes. To scale the algorithms, “reference values” will be defined that represent normal conditions for each operation unit. To support and underpin the model developments, we use a relational exposure database in Access. The database is organized according to the described concept of operation units, related determinants, and control measures. Exposure information is collected from occupational hygienists of Arbo Unie, TNO archives, other consultants, and branches that participate in the so called VASt program (program of the Dutch government to assist SMEs in reinforcing the working conditions). Our approach to enlist a number of active stakeholders to provide exposure measurements for inclusion in a publicly available database appeared to be feasible. The collation of data is an ongoing process. At present, the database contains approximately 2000 measurements with contextual information. The database will expand in the coming months. The database will be used for validation purposes and derivation of operation unit specific reference values. The operation unit approach, the use of the exposure database, and its limitations are discussed.

Experimental Validation of the Consumer Exposure Modeling Tool ConsExpo

MAB2-PD-02 ConsExpo is a computer program designed to estimate exposure of consumers to chemical substances in consumer products. The software implements generic, multi-tier models for inhalation, oral, and dermal routes of exposure. In addition, the program includes a database with compiled data and suggested defaults on exposure scenarios and exposure factors for different product groups. The current version (4.1) of the software includes data on cosmetics, pest control products, cleaning products, and disinfectants. In the absence of accurate and representative monitoring data, exposure to chemicals from consumer products has often to be done by modeling. Although a real validation of any exposure estimation is never completely achievable, it is of utmost importance that models are at least evaluated with respect to their performance under controlled conditions and that their limitations are made clear. At present, the inhalation exposure models of ConsExpo are being validated in this sense. Experiments on residential exposure to aerosols from spray products have been concluded and have led to adjustments of the aerosol model. Experiments on the air concentrations resulting from evaporation of chemical substances from liquid products such as cleaning products and paints are currently being performed. Aerosol exposure experiments have been conducted in a climatically controllable room for products such as insect sprays, hair sprays, deodorants, cleaning products, and paints. Resulting air concentration profiles and important determinants of exposure such as droplet size distributions and mass generation rates of the different spray products will be presented. The ConsExpo model describing the inhalation exposure to aerosols has been adjusted and was found to describe the experimental data well. Experiments on exposure to chemicals substances evaporating from liquid matrices representative of products, such as paints and cleaning products, are conducted in a room for which ventilation and temperature can be accurately controlled. The current models describing evaporation are tested against the measured air concentrations, and their performance is evaluated.

Pulmonary and Systemic Responses to Inhaled Allergens are Aggravated by Inhaled Endotoxin

RATIONALE: It has been suggested that specific properties of cockroach allergens can lead to allergic sensitization rather than immune tolerance upon repeated inhalation. Also, it is believed that co-exposure to allergens and other noxious environmental agents, such as endotoxin, can upregulate this allergic response. We utilized newborn/juvenile murine inhalation exposure models developed in our laboratory to test these hypotheses.

INHALATION EXPOSURE TO VOLATILE CHEMICALS IN DRINKING WATER

Inhalation of volatile chemicals released during household water use is a recognized exposure pathway. Models previously developed to estimate inhalation exposure to radon gas, radon progeny, and volatile organic compounds (VOCs) were limited in their ability to predict exposure to compounds of low volatility due to a lack of appropriate experimental data. Recently, a comprehensive series of experimental studies has been completed in which mass-transfer coefficients for a shower, bath, faucet, washing machine, and dishwasher have been measured, making more detailed and accurate predictions possible. In this paper, the theoretical basis for mass transfer between water and air is reviewed and then extended to include the pH-dependent transfer of volatile compounds that participate in rapid acid/base reactions. This class of compound has not previously been considered in exposure assessment models. The evolution of inhalation exposure models is briefly reviewed and an improved version is developed. Sample calculations are made demonstrating the influence of both low volatility and pH on inhalation exposure. The paper concludes with illustrative examples assessing the toxicological implications of exposure to radon and hydrogen cyanide. The analysis confirms that inhalation is an important exposure pathway for waterborne chemicals.

Workshop on harmonization of serving future needs with occupational exposure databases--inhalation modeling, session IIIA.

This workshop was one of several that took place at the International Symposium on Occupational Exposure Databases and Their Application for the Next Millennium held in London from November 1-3, 1999. About 30 delegates participated in the workshop. The agenda for the discussions was provided by a white paper prepared by the organizers. The workshop produced a conceptual outline for a general-purpose prediction model for inhalation exposure, and constructed a list of important input variables for successful model development. Evaluation of prototype models was discussed in some detail, and the workshop concluded with suggestions for taking forward the ideas discussed and maintaining the momentum and interest generated during the symposium.

A Distributed Parameter Physiologically‐Based Pharmacokinetic Model for Dermal and Inhalation Exposure to Volatile Organic Compounds

Estimates of dermal dose from exposures to toxic chemicals are typically derived using models that assume instantaneous establishment of steady‐state dermal mass flux. However, dermal absorption theory indicates that this assumption is invalid for short‐term exposures to volatile organic chemicals (VOCs). A generalized distributed parameter physiologically‐based pharmacokinetic model (DP‐PBPK), which describes unsteady state dermal mass flux via a partial differential equation (Fickian diffusion), has been developed for inhalation and dermal absorption of VOCs. In the present study, the DP‐PBPK model has been parameterized for chloroform, and compared with two simpler PBPK models of chloroform. The latter are lumped parameter models, employing ordinary differential equations, that do not account for the dermal absorption time lag associated with the accumulation of permeant chemical in tissue represented by permeability coefficients. All three models were evaluated by comparing simulated post‐exposure exhaled breath concentration profiles with measured concentrations following environmental chloroform exposures. The DP‐PBPK model predicted a time‐lag in the exhaled breath concentration profile, consistent with the experimental data. The DP‐PBPK model also predicted significant volatilization of chloroform, for a simulated dermal exposure scenario. The end‐exposure dermal dose predicted by the DP‐PBPK model is similar to that predicted by the EPA recommended method for short‐term exposures, and is significantly greater than the end‐exposure dose predicted by the lumped parameter models. However, the net dermal dose predicted by the DP‐PBPK model is substantially less than that predicted by the EPA method, due to the post‐exposure volatilization predicted by the DP‐PBPK model. Moreover, the net dermal dose of chloroform predicted by all three models was nearly the same, even though the lumped parameter models did not predict substantial volatilization.